Superovulation with human chorionic gonadotropin (hCG) trigger and gonadotropin releasing hormone agonist (GnRHa) trigger differentially alter essential angiogenic factors in the endometrium in a mouse ART model†.

Gonadotropin-releasing hormone agonists (GnRHa) are used as an alternative to human chorionic gonadotropin (hCG) to trigger ovulation and decrease the risk of ovarian hyperstimulation syndrome. GnRHa is less potent at inducing ovarian vascular endothelial growth factor (VEGF), but may also affect endometrial angiogenesis and early placental development. In this study, we explore the effect of superovulation on endometrial angiogenesis during critical periods of gestation in a mouse model. We assigned female mice to three groups: natural mating or mating following injection with equine chorionic gonadotropin and trigger with GnRHa or hCG trigger. Females were killed prior to implantation (E3.5), post-implantation (E7.5), and at midgestation (E10.5), and maternal serum, uterus, and ovaries were collected. During peri-implantation, endometrial Vegfr1 and Vegfr2 mRNA were significantly increased in the GnRHa trigger group (P < 0.02) relative to the hCG group. Vegfr1 is highly expressed in the endometrial lining and secretory glands immediately prior to implantation. At E7.5, the ectoplacental cone expression of Vegfa and its receptor, Vegfr2, was significantly higher in the hCG trigger group compared to the GnRHa group (P < 0.05). Soluble VEGFR1 and free VEGFA were much higher in the serum of mice exposed to the hCG trigger compared to GnRHa group. At midgestation, there was significantly more local Vegfa expression in the placenta of mice triggered with hCG. GnRHa and hCG triggers differentially disrupt the endometrial expression of key angiogenic factors during critical periods of mouse gestation. These results may have significant implications for placental development and neonatal outcomes following human in vitro fertilization.

Interplay of transcriptional signaling by progesterone, cyclic AMP, and inflammation in myometrial cells: implications for the control of human parturition.

Parturition involves cellular signaling changes driven by the complex interplay between progesterone (P4), inflammation, and the cyclic adenosine monophosphate (cAMP) pathway. To characterize this interplay, we performed comprehensive transcriptomic studies utilizing eight treatment combinations on myometrial cell lines and tissue samples from pregnant women. We performed genome-wide RNA-sequencing on the hTERT-HM${}^{A/B}$ cell line treated with all combinations of P4, forskolin (FSK) (induces cAMP), and interleukin-1$\beta$ (IL-1$\beta$). We then performed gene set enrichment and regulatory network analyses to identify pathways commonly, differentially, or synergistically regulated by these treatments. Finally, we used tissue similarity index (TSI) to characterize the correspondence between cell lines and tissue phenotypes. We observed that in addition to their individual anti-inflammatory effects, P4 and cAMP synergistically blocked specific inflammatory pathways/regulators including STAT3/6, CEBPA/B, and OCT1/7, but not NF$\kappa$B. TSI analysis indicated that FSK + P4- and IL-1$\beta$-treated cells exhibit transcriptional signatures highly similar to non-laboring and laboring term myometrium, respectively. Our results identify potential therapeutic targets to prevent preterm birth and show that the hTERT-HM${}^{A/B}$ cell line provides an accurate transcriptional model for term myometrial tissue.

Progestin therapy to prevent preterm birth: History and effectiveness of current strategies and development of novel approaches.

In the 1930s the "progestin" hormone produced by the corpus luteum was isolated and found to be a Δ4-keto-steroid. It was aptly named progesterone (P4) and in the following 30 years the capacity of P4 and derivatives to prevent preterm birth (PTB) was examined. Outcomes of multiple small studies suggested that progestin prophylaxis beginning at mid-gestation decreases the risk for PTB. Subsequent larger trials found that prophylaxis with weekly intramuscular injections of 17α-hydroxyprogesterone caproate (17HPC) beginning at mid-gestation decreased PTB risk in women with a history of PTB. Other trials found that daily vaginal P4 prophylaxis, also beginning at mid-gestation decreased PTB risk in women with a short cervix. Currently, prophylaxis with 17HPC (in women with a history of PTB) or vaginal P4 (in women with a short cervix) are used to prevent PTB. Recent advances in understanding the molecular biology of P4 signaling in uterine cells is revealing novel progestin-based targets for PTB prevention. One possibility is to use selective P4 receptor (PR) modulators (SPRMs) to boost PR anti-inflammatory activity that blocks labor, while simultaneously preventing PR phosphorylation that causes loss of P4/PR anti-inflammatory activity. This may be achieved by SPRMs that induce a specific PR conformation that prevents site-specific serine phosphorylation that inhibits anti-inflammatory activity. Further advances in understanding how P4 promotes uterine quiescence and how its labor blocking actions are withdrawn to trigger parturition will reveal novel therapeutic targets to more effectively prevent PTB.

Progesterone and cAMP synergize to inhibit responsiveness of myometrial cells to pro-inflammatory/pro-labor stimuli.

Progesterone (P4) acting through the P4 receptor (PR) isoforms, PR-A and PR-B, promotes uterine quiescence for most of pregnancy, in part, by inhibiting the response of myometrial cells to pro-labor inflammatory stimuli. This anti-inflammatory effect is inhibited by phosphorylation of PR-A at serine-344 and -345 (pSer344/345-PRA). Activation of the cyclic adenosine monophosphate (cAMP) signaling pathway also promotes uterine quiescence and myometrial relaxation. This study examined the cross-talk between P4/PR and cAMP signaling to exert anti-inflammatory actions and control pSer344/345-PRA generation in myometrial cells. In the hTERT-HMA/B immortalized human myometrial cell line P4 inhibited responsiveness to interleukin (IL)-1ß and forskolin (increases cAMP) and 8-Br-cAMP increased this effect in a concentration-dependent and synergistic manner that was mediated by activation of protein kinase A (PKA). Forskolin also inhibited the generation of pSer344/345-PRA and expression of key contraction-associated genes. Generation of pSer344/345-PRA was catalyzed by stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK). Forskolin inhibited pSer344/345-PRA generation, in part, by increasing the expression of dual specificity protein phosphatase 1 (DUSP1), a phosphatase that inactivates mitogen-activated protein kinases (MAPKs) including SAPK/JNK. P4/PR and forskolin increased DUSP1 expression. The data suggest that P4/PR promotes uterine quiescence via cross-talk and synergy with cAMP/PKA signaling in myometrial cells that involves DUSP1-mediated inhibition of SAPK/JNK activation.

Effect of treatment of iron deficiency anemia onhemoglobin A1c in type 2 diabetic patients

Background/aim: Iron deficiency anemia (IDA) affects hemoglobin A1c (HbA1c) levels. This study aimed to evaluate the effect of treatment of iron deficiency anemia on hemoglobin A1c in type 2 diabetic patients.Materials and methods: Ninety type 2 diabetes mellitus (T2DM) patients with IDA were included in a randomized, placebo-controlled, single-blind clinical trial. The intervention group (n = 45) received 200 mg/day oral iron for 3 months and the control group (n = 45) received an oral placebo for the same period. Fasting blood sugar, complete blood count, and HbA1c were measured for all subjects at the beginning and the end of the trial.Results: The mean age of the treatment and control group was 51.47 ± 1.05 and 52 ± 1.1 years, respectively. The two groups were not statistically significantly different with regard to diabetes duration (P = 0.436) and age (P = 0.617). Hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin, serum iron, ferritin, total iron-binding capacity, and HbA1c were significantly improved in the intervention group in comparison with the control group (P = 0.005).Conclusion: Iron status should be considered during the interpretation of the HbA1c concentrations in diabetes mellitus. Iron replacement therapy can decrease HbA1c in anemic patients with IDA and T2DM.

Transitional Meningioma After Fetal Liver-Derived Cell Suspension Allotransplant: A Case Report.

Diabetes mellitus is a disease with no definite cure. In recent years, stem cell transplant has led to treatment of various diseases including diabetes. We sought to report a type 1 diabetic patient with a brain mass, diagnosed as transitional meningioma, after a fetal hematopoietic stem cell transplant. A 57-year-old woman with type 1 diabetes who previously had undergone a fetal hematopoietic stem cell transplant, attended the clinic with a history of progressive bifrontal headaches accompanied by nausea, vomiting, and visual disturbances over the previous 8 months. Investigations revealed a 2-cm mass in the right temporal region. The patient underwent a craniotomy, and the lesion was removed and sent for pathological and genetic investigations. The results indicated transitional meningioma with the origin of transplanted fetal hematopoietic stem cells. To our knowledge, this is the first report of transitional meningioma as a result of stem cell transplant. Despite all unanswered questions about the safety of stem cell transplant, this novel therapy provides hope for patients with type 1 diabetes.

Inflammatory Stimuli Increase Progesterone Receptor-A Stability and Transrepressive Activity in Myometrial Cells.

The steroid hormone progesterone acting via the nuclear progesterone receptor (PR) isoforms, progesterone receptor A (PR-A) and progesterone receptor B (PR-B), is essential for the maintenance of uterine quiescence during pregnancy. Inhibition of PR signaling augments uterine contractility and induces labor. Human parturition is thought to be triggered by modulation of PR signaling in myometrial cells to induce a functional progesterone withdrawal. One mechanism for functional progesterone withdrawal is increased abundance of PR-A, which decreases progesterone responsiveness by inhibiting the transcriptional activity of PR-B. Human parturition also involves tissue-level inflammation within the myometrium. This study examined the control of PR-A abundance and transrepressive activity in myometrial cells and the role of the inflammatory stimuli in the form of interleukin-1ß (IL-1ß) and lipopolysaccharide (LPS) in these processes. We found that abundance of PR-A was markedly increased by progesterone and by exposure to IL-1ß and LPS via posttranslational mechanisms involving increased PR-A protein stability. In contrast, progesterone decreased abundance of PR-B by increasing its rate of degradation. Together, progesterone and proinflammatory stimuli induced a PR-A-dominant state in myometrial cells similar to that observed in term laboring myometrium. IL-1ß and LPS also increased the capacity for PR-A to inhibit the transcriptional activity of PR-B. Taken together, our data suggest that proinflammatory stimuli increase the steady-state levels of PR-A and its transrepressive activity in myometrial cells and support the hypothesis that tissue-level inflammation triggers parturition by inducing PR-A-mediated functional progesterone withdrawal.

Human Parturition Involves Phosphorylation of Progesterone Receptor-A at Serine-345 in Myometrial Cells.

The hypothesis that phosphorylation of progesterone receptor (PR) isoforms, PR-A and PR-B, in myometrial cells affects progesterone action in the context of human parturition was tested. Immunodetection of phosphoserine (pSer) PR forms in term myometrium revealed that the onset of labor is associated with increased phosphorylation of PR-A at serine-345 (pSer345-PRA) and that pSer345-PRA localized to the nucleus of myometrial cells. In explant cultures of term myometrium generation of pSer345-PRA was induced by interleukin-1ß and dependent on progesterone, suggesting that pSer345-PRA generation is induced by a proinflammatory stimulus. In the hTERT-HMA/B human myometrial cell line, abundance of pSer345-PRA was induced by progesterone in a dose- (EC50 ∼1 nM) and time-dependent manner. Prevention of pSer345 (by site-directed mutagenesis) abolished the capacity for PR-A to inhibit anti-inflammatory actions of progesterone mediated by PR-B but had no effect on the transrepressive activity of PR-A at a canonical progesterone response element. Taken together, the data show that human parturition involves the phosphorylation of PR-A at serine-345 in myometrial cells and that this process is ligand dependent and induced by a proinflammatory stimulus. We also found that in myometrial cells, pSer345 activates the capacity for PR-A to inhibit antiinflammatory actions of progesterone mediated by PR-B. Phosphorylation of PR-A at serine-345 may be an important functional link between tissue-level inflammation and PR-A-mediated functional progesterone withdrawal to trigger parturition.

Effect of vitamins C and E on insulin resistance in diabetes: a meta-analysis study.

BACKGROUND: Data regarding the effect of vitamin C (VC) and vitamin E (VE) supplementation on insulin resistance in type 2 diabetes mellitus (T2DM) are controversial. We aimed to systematically review the current data on this topic. MATERIALS AND METHODS: All randomized controlled trials (RCTs) conducted to assess the effect of VC and/or VE on insulin resistance in diabetes published in Google Scholar and PubMed web databases until January 2014 were included. Exclusion criteria were studies conducted in animal, type 1 DM, children or pregnant women. Main outcome measure was insulin resistance by homoeostasis model assessment (HOMA) index. According to degree of heterogeneity, fixed- or random-effect model was employed by stata software (11.0). RESULTS: We selected 14 RCTs involving 735 patients with T2DM. VE or mixture-mode supplementation did not have any significant effect on HOMA with a standardized mean difference (SMD): 0·017, 95% CI: -0·376 to 0·411 (P = 0·932); and SMD: -0·035, 95% CI: -0·634 to 0·025 (P = 0·070), respectively, by random-effect model. VC supplement alone did not improve insulin resistance with a SMD: -0·150, 95% CI: -0·494 to 0·194 (P = 0·391), by fixed-effect model. Meta-regression test demonstrated that HOMA index may have not been influenced by the year of publication, dosage or duration of treatment. CONCLUSIONS: The sole intake of VC, VE or their combination with other antioxidants could not improve insulin resistance in diabetes.

Evaluation of fetal cell transplantation safety in treatment of diabetes: a three-year follow-up.

BACKGROUND: Rapidly increasing prevalence of diabetes throughout the world highlights the importance of looking for new treatment options for the disease such as stem cell therapy. With regard to the increasing attention towards stem-cell therapy as a curative treatment for diabetes in recent years, it is of crucial importance to ensure the safety of this novel therapeutic technique. In this study we aim to evaluate the safety of fetal liver-derived cell suspension allotransplantation in the diabetic patients who had attended a clinical trial in 2007. METHODS: 44 out of a total number of 56 patients who had undergone either fetal liver-derived cell suspension allotransplantation or placebo injection in 2007 (IRCT number: 138811071414 N10) were contacted and recruited for the evaluation of possible complications. Patients were referred to a designated ophthalmologist and cardiologist to be screened for retinopathy and cardiovascular diseases. 24-hour urine was collected and tested for the evaluation of nephropathy; and, neuropathy was assessed by means of neuropathic symptoms and monofilament test. RESULTS: There were no life-threatening complications nor significant differences in terms of evaluated diabetes complications ( retinopathy, neuropathy, nephropathy and cardiovascular diseases ) between the case and control groups. However, one case of meningioma was reported. CONCLUSIONS: Findings of our study demonstrated that stem cell transplantation can be considered a relatively safe procedure apart from one case of meningioma; it did neither cause any life-threatening complications nor increased the rate of the diabetes micro- and macrovascular complications.

The Association of Serum Total Peptide YY (PYY) with Obesity and Body Fat Measures in the CODING Study.

BACKGROUND: PYY is an appetite suppressing hormone. Low circulating PYY has been linked to greater BMI. However data is controversial and this association has not been verified in large human populations. OBJECTIVE: The purpose of this study was to investigate if fasting serum total PYY is associated with obesity status and/or adiposity at the population level. DESIGN: A total of 2094 subjects (Male-523, Female-1571) participated in this investigation. Total PYY was measured in fasting serum by enzyme-linked immunosorbent assay. Obesity status (NW-normal-weight, OW-overweight and OB-obese) was determined by the Bray Criteria according to body fat percentage measured by dual-energy x-ray absorptiometry and the WHO criteria according to BMI. One-way ANOVA and multiple regression was used to assess the adiposity-specific association between PYY and the following; weight, BMI, waist-circumference, hip-circumference, waist-hip ratio, percent body fat (%BF), trunk fat (%TF), android fat (%AF) and gynoid fat (%GF). RESULTS: PYY was not significantly different among NW, OW and OB groups defined by neither %BF nor BMI for both men and women. However among women, fasting PYY was positively associated with adiposity measures. Women with the highest (Top 33%) waist-circumference, %BF and %TF had significantly higher PYY (10.5%, 8.3% and 9.2% respectively) than women with the lowest (Bottom 33%). Age, smoking, medication use and menopause were all positively associated with PYY levels in women but not in men. CONCLUSION: To our knowledge this is the largest population based study, with the most comprehensive analysis and measures of confounding factors, to explore the relationship of circulating PYY with obesity. Contrary to initial findings in the literature we discovered that PYY was positively associated with body fat measures (waist-circumference, %BF and %TF) in women. Although the effect size of the positive association of PYY with obesity in women is small, and potentially negligible, it may in fact represent a protective response against significant weight gain.

A randomized, placebo-controlled trial of selenium supplementation in patients with type 2 diabetes: effects on glucose homeostasis, oxidative stress, and lipid profile.

Selenium is an antioxidant trace element. Patients with diabetes are shown to have increased oxidative stress together with decreased selenium concentrations. Whether raising serum selenium will improve blood glucose management in diabetes is largely unknown. In this randomized, double-blind placebo-controlled trial, we assessed the effects of selenium on blood glucose, lipid profile, and oxidative stress in 60 patients with type 2 diabetes. Selenium 200 µg/d or placebo was administered orally for 3 months. Serum concentrations of fasting plasma glucose, glycosylated hemoglobin A1c (HbA1c), insulin, and lipid profile, as well as ferric-reducing ability of plasma and thiobarbituric acid-reactive substances were determined in the fasting state at baseline and after 3 months. Mean (SD) serum selenium at baseline was 42.69 (29.47) µg/L and 47.11 (42.86) µg/L in selenium and placebo groups, respectively. At endpoint, selenium concentration reached to 71.98 (45.08) µg/L in selenium recipients compared with 45.38 (46.45) µg/L in placebo recipients (P<0.01). Between-group comparison showed that fasting plasma glucose, glycosylated hemoglobin A1c, and high-density lipoprotein cholesterol were statistically significantly higher in the selenium recipient arm. Other endpoints changes during the course of trial were not statistically different across the 2 treatment arms. This study suggests that selenium supplementation in patients with type 2 diabetes may be associated with adverse effects on blood glucose homeostasis, even when plasma selenium concentration is raised from deficient status to the optimal concentration of antioxidant activity. Until results of further studies become available, indiscriminate use of selenium supplements in patients with type 2 diabetes warrants caution.

Beneficial association of serum ghrelin and peptide YY with bone mineral density in the Newfoundland population.

BACKGROUND: Ghrelin and peptide YY (PYY) are appetite regulating hormones secreted from the gastrointestinal tract (gut). Aside from their known effect on energy homeostasis, accumulating data indicates that these gut hormones also affect bone metabolism. However, data regarding the influence of ghrelin and PYY on bone density in humans is very limited, and the results are inconclusive. Therefore, this study was designed to investigate the potential association between circulating ghrelin and PYY with bone density indices in the general population. METHODS: A total of 2257 adult subjects from the CODING (Complex Diseases in the Newfoundland Population: Environment and Genetics) study participated in this investigation. Acylated ghrelin and total PYY were measured in serum after a 12-hour fasting, with the Enzyme- Linked Immunosorbent Assay (ELISA) method. Bone mineral density was measured by dual-energy X-ray absorptiometry at the spine, femoral neck, and total hip. Multiple regression analyses adjusting for age, BMI, physical activity, smoking, and alcohol consumption were employed to analyze the association between serum ghrelin and PYY with bone mineral density parameters. RESULTS: Significant positive associations of ghrelin concentration with L2-L4 BMD, L2-L4 Z-score, femoral neck BMD, femoral neck Z-score, total hip BMD, and total hip Z-score were found in women. No significant correlations between ghrelin and bone density indices were present in men. After dividing the female group into pre-menopausal and post-menopausal, ghrelin was positively correlated with femoral neck Z-score, and total hip Z-score in pre-menopausal women and L2-L4 BMD, and Z-score in post-menopausal group. Moreover, no significant association was discovered between serum PYY and bone density at any site. CONCLUSION: Our results suggest a beneficial association of circulating ghrelin concentration with bone density in women at the population level. This association is independent of major confounding factors including BMI, physical activity, age, alcohol consumption, and smoking. Effect of menopause on this association seemed to be site specific. However, PYY does not seem to be associated with bone density parameters.

Food addiction: its prevalence and significant association with obesity in the general population.

BACKGROUND: 'Food addiction' shares a similar neurobiological and behavioral framework with substance addiction. However whether, and to what degree, 'food addiction' contributes to obesity in the general population is unknown. OBJECTIVES: to assess 1) the prevalence of 'food addiction' in the Newfoundland population; 2) if clinical symptom counts of 'food addiction' were significantly correlated with the body composition measurements; 3) if food addicts were significantly more obese than controls, and 4) if macronutrient intakes are associated with 'food addiction'. DESIGN: A total of 652 adults (415 women, 237 men) recruited from the general population participated in this study. Obesity was evaluated by Body Mass Index (BMI) and Body Fat percentage measured by dual-energy X-ray absorptiometry. 'Food addiction' was assessed using the Yale Food Addiction Scale and macronutrient intake was determined from the Willet Food Frequency Questionnaire. RESULTS: The prevalence of 'food addiction' was 5.4% (6.7% in females and 3.0% in males) and increased with obesity status. The clinical symptom counts of 'food addiction' were positively correlated with all body composition measurements across the entire sample (p<0.001). Obesity measurements were significantly higher in food addicts than controls; Food addicts were 11.7 (kg) heavier, 4.6 BMI units higher, and had 8.2% more body fat and 8.5% more trunk fat. Furthermore, food addicts consumed more calories from fat and protein compared with controls. CONCLUSION: Our results demonstrated that 'food addiction' contributes to severity of obesity and body composition measurements from normal weight to obese individuals in the general population with higher rate in women as compared to men.

Short-term overfeeding increases circulating adiponectin independent of obesity status.

BACKGROUND: Adiponectin is an adipose tissue derived hormone which strengthens insulin sensitivity. However, there is little data available regarding the influence of a positive energy challenge (PEC) on circulating adiponectin and the role of obesity status on this response. OBJECTIVE: The purpose of this study was to investigate how circulating adiponectin will respond to a short-term PEC and whether or not this response will differ among normal-weight(NW), overweight(OW) and obese(OB). DESIGN: We examined adiponectin among 64 young men (19-29 yr) before and after a 7-day overfeeding (70% above normal energy requirements). The relationship between adiponectin and obesity related phenotypes including; weight, percent body fat (%BF), percent trunk fat (%TF), percent android fat (%AF), body mass index (BMI), total cholesterol, HDLc, LDLc, glucose, insulin, homeostatic model assessment insulin resistance (HOMA-IR) and ß-cell function (HOMA-ß) were analyzed before and after overfeeding. RESULTS: Analysis of variance (ANOVA) and partial correlations were used to compute the effect of overfeeding on adiponectin and its association with adiposity measurements, respectively. Circulating Adiponectin levels significantly increased after the 7-day overfeeding in all three adiposity groups. Moreover, adiponectin at baseline was not significantly different among NW, OW and OB subjects defined by either %BF or BMI. Baseline adiponectin was negatively correlated with weight and BMI for the entire cohort and %TF, glucose, insulin and HOMA-IR in OB. However, after controlling for insulin resistance the correlation of adiponectin with weight, BMI and %TF were nullified. CONCLUSION: Our study provides evidence that the protective response of adiponectin is preserved during a PEC regardless of adiposity. Baseline adiponectin level is not directly associated with obesity status and weight gain in response to short-term overfeeding. However, the significant increase of adiponectin in response to overfeeding indicates the physiological potential for adiponectin to attenuate insulin resistance during the development of obesity.

Circulating glucagon-like peptide-1 increases in response to short-term overfeeding in men.

BACKGROUND: Glucagon-like Peptide-1 (GLP-1) is an incretin hormone secreted from the gastrointestinal tract that facilitates the glucose-dependent insulin response. Additionally, GLP-1 is thought to be involved in energy homeostasis. Currently little is known about GLP-1's responsiveness to an energy surplus, a fundamental cause of obesity and diabetes. Our objective was to examine the response of serum GLP-1 to short-term (7 day) overfeeding in young men. METHODS: Seventy-two young men from the Canadian province of Newfoundland were recruited for the study. For 7-days, the subjects consumed 70% more calories than required at baseline.Various measurements including: anthropometrics, body composition, markers of glucose/lipid metabolism and serum total GLP-1, were taken at a fasted state before (day 1) and after (day 8) the challenge. Paired t-test analyses were used to assess the change in variables after the overfeeding period. Additionally, the relationship between serum GLP-1 and the measured variables at baseline and change due to overfeeding were analyzed. RESULTS: Serum GLP-1 was significantly increased in all groups in response to the 7-day energy surplus, indicating the increase was independent of adiposity status. There was no significant difference in fasting GLP-1 at baseline between the normal weight and overweight/obese groups. At baseline, GLP-1 concentration negatively correlated with HDL-cholesterol and positively correlated with triacylglycerols and markers of insulin resistance in the overweight/obese group. Also GLP-1 was negatively correlated with change in percent gynoid fat in the overweight/obese subjects. Percent change in GLP-1 was negatively associated with percent change in gynoid fat in the normal weight group and positively associated with percent change in cholesterol in the overweight/obese group. Percentage change of circulating triacylglycerols was positively associated with percent change in GLP-1 in both adiposity groups. CONCLUSION: Our findings showed that GLP-1 serum concentration is not a significant factor in determining obesity status. The increase of GLP-1 in all subjects regardless of obesity status, suggest GLP-1 serves as a protective role, counteracting energy surplus.

Serum acylated ghrelin is negatively correlated with the insulin resistance in the CODING study.

OBJECTIVE: Ghrelin is a 28-amino acid orexigenic peptide synthesized mainly in the stomach. Acute administration of ghrelin has been found to decrease insulin secretion. However, little data is available regarding whether ghrelin contributes to the long-term regulation of insulin resistance at the population level. The aim of this study is to investigate the association between circulating ghrelin and insulin resistance in a large population based study. DESIGN: A total of 2082 CODING study (Complex Diseases in the Newfoundland population: Environment and Genetics) subjects were assessed. Subjects were of at least third generation Newfoundland descent, between the ages of 20 and 79 years, and had no serious metabolic, cardiovascular, or endocrine diseases. Ghrelin was measured with an Enzyme Immunoassay method. Insulin and fasting glucose were measured by Immulite 2500 autoanalyzer and Lx20 clinical chemistry analyzer, respectively. Homeostatic Model Assessment of ß cell function (HOMA-ß) and Insulin Resistance (HOMA-IR) and Quantitative Insulin-sensitivity Check Index (QUICKI) were used for measurement of insulin resistance. RESULTS: Partial correlation analyses showed a significant negative correlation between circulating ghrelin and insulin level and insulin resistance in the entire cohort and also in men and women separately. The aforementioned correlation was independent of age, percentage of trunk fat and HDL-cholesterol. According to menopausal status, only pre-menopausal women revealed negative correlations. CONCLUSION: Our results suggest that except for postmenopausal women, high circulating ghrelin level is associated with lower insulin resistance in the general population.

Serum acylated ghrelin concentrations in response to short-term overfeeding in normal weight, overweight, and obese men.

BACKGROUND: Ghrelin, an orexigenic gut hormone secreted primarily from the stomach, is involved in energy homeostasis. However, little data is available regarding its response to energy surplus and the development of human obesity. OBJECTIVE: The present study investigated the response of circulating acylated ghrelin to a 7-day positive energy challenge. DESIGN: A total of 68 healthy young men were overfed 70% more calories than required, for 1-week. Subjects were classified based on percent body fat (measured by dual-energy X-ray absorptiometry) as normal weight, overweight, and obese. Serum acylated ghrelin concentration was measured before and after the positive energy challenge. Additionally, the relationship between acylated ghrelin and obesity-related phenotypes including weight, body mass index, percent body fat, cholesterol, HDL-c, LDL-c, glucose, insulin and homeostasis model assessment of insulin resistance and ß-cell function at baseline and change due to overfeeding, were assessed. RESULTS: Contrary to our expectations, serum acylated ghrelin was significantly increased in response to overfeeding and the increase was independent of obesity status. There was no significant difference in fasting acylated ghrelin between normal weight, overweight, and obese men at baseline. Acylated ghrelin was negatively correlated with weight and BMI for normal weight and with BMI in overweight men. Also ghrelin was correlated with change in weight and BMI in overweight (negative relationship) and obese (positive relationship) groups. CONCLUSION: Our results showed that circulating acylated ghrelin was increased after a 7-day positive energy challenge regardless of adiposity status. However, acylated ghrelin was correlated with change in weight and BMI in opposing directions, in overweight and obese subjects respectively, thus dependent on obesity status.

Stem cell therapy in treatment of different diseases.

Stem cells are undifferentiated cells with the ability of proliferation, regeneration, conversion to differentiated cells and producing various tissues. Stem cells are divided into two categories of embryonic and adult. In another categorization stem cells are divided to Totipotent, Multipotent and Unipotent cells.So far usage of stem cells in treatment of various blood diseases has been studied (such as lymphoblastic leukemia, myeloid leukemia, thalassemia, multiple myeloma and cycle cell anemia). In this paper the goal is evaluation of cell therapy in treatment of Parkinson's disease, Amyotrophic lateral sclerosis, Alzheimer, Stroke, Spinal Cord Injury, Multiple Sclerosis, Radiation Induced Intestinal Injury, Inflammatory Bowel Disease, Liver Disease, Duchenne Muscular Dystrophy, Diabetes, Heart Disease, Bone Disease, Renal Disease, Chronic Wounds, Graft-Versus-Host Disease, Sepsis and Respiratory diseases. It should be mentioned that some disease that are the target of cell therapy are discussed in this article.

Relationship between gamma-glutamyl transferase and glucose intolerance in first degree relatives of type 2 diabetics patients.

BACKGROUND: Considering that serum gamma-glutamyl transferase (GGT) activity could reflect several different processes relevant to diabetes pathogenesis and the increasing rate of type 2 diabetes worldwide, the aim of this study was to assess the association between serum GGT concentrations and glucose intolerance, in the first-degree relatives (FDR) of type 2 diabetic patients. METHODS: In this descriptive study, 30-80 years old, non diabetic FDRs of type 2 diabetic patients were studied. Serum GGT was measured by enzymatic photometry method in all studied population. The relationship between GGT and glucose intolerance status (normal, prediabetic and diabetics) was evaluated. RESULTS: During this study 551 non-diabetic FDRs of type 2 diabetic patients were studied. Mean of GGT was 25.3 ± 12.1 IU/L. According to glucose tolerance test, 153 were normal and 217 and 181 were diabetic and prediabetic respectively. Mean of GGT in normal, prediabetic and diabetic patients was 23.5 ± 15.9 IU/L, 29.1 ± 28.1 IU/L and 30.9 ± 24.8 IU/L respectively (p = 0.000). The proportion of prediabetic and diabetic patients was higher in higher quartile of GGT and there was a significant correlation between GGT and BMI, HbA1c, FPG, cholesterol, LDL-C, and triglyceride (p < 0.05). There was a significant relation between GGT and area under the curve (AUC) of oral glucose tolerance test (p = 0.00). CONCLUSIONS: Measurement of GGT in FDRs of type 2 diabetic patients may be useful in assessing the risk of diabetes; those with chronically high levels of GGT should be considered as high risk group for diabetes.